Injection molding process for the preparation of an oral delivery device for a pharmaceutically active agent

ABSTRACT

An injection moulding process for the preparation of an oral delivery device comprising a core which contains a pharmaceutically active agent, having a coating with one or more openings leading to such a core. The invention also relates to devices produced by the process, and to injection moulds suitable for performing the process.

The present invention relates to a novel process for the preparation ofan oral delivery device for a pharmaceutically active agent. Inparticular, the invention relates to a process for the preparation of anoral delivery device comprising a core which contains the active agent,having a coating with one or more openings leading to such a core. Theinvention also relates to novel oral delivery devices obtainable by theprocess of this invention.

The coating of tablet cores comprising an active agent, for example toprepare a pharmaceutical tablet for oral administration, is wellestablished practice. The common reasons for so doing include: improvedproduct mechanical integrity; improved stability to the surroundingenvironment (particularly air, moisture and light); a means of modifyingthe release rate of the active agent; and in order to achievedistinctive or improved aesthetic characteristics. Processes for coatingare also well established in the art.

Of the factors described above, the use of a coating to control the rateof release of an active agent has received considerable attention and,indeed, many different devices have been developed for such a purpose.Some of the devices utilised are discussed in U.S. Pat. No. 5,004,614.This patent describes a controlled release device with an impermeablecoating having an orifice for release of drug when the device has beenorally administered and is immersed in an aqueous medium such asgastro-intestinal fluid. Such devices are prepared either according topressure coating or dip coating methods and the orifice is formed byremoving sections of the formed coating with laser or mechanicaldrilling techniques.

It is an object of this invention to provide an alternative process forthe preparation of devices of the above described type. It is aparticular object of this invention to provide an improved process forthe manufacture of devices of the type disclosed in U.S. Pat. No.5,004,614, the contents of which are incorporated herein by reference.It is also an object of the invention to provide novel constructions ofdevices of this general type. Other objects and advantages of theinvention will become apparent from the following description.

The present invention therefore provides, in a first aspect, a processfor the preparation of a delivery device comprising a core whichincludes a pharmaceutically active agent covered by an outer coatingwhich includes one or more openings communicating from the exterior ofthe device to the core characterised in that the outer coating isapplied by injection moulding said coating around said core.

A process for making a device according to this invention may, forexample, comprise the steps of:

providing, if necessary preparing, the core of the device comprising apharmaceutically active agent;

locating said core within a mould cavity surrounding the core, saidmould cavity defining the required dimensions of the outer coating andpreferably also defining the required position, shape and dimensions ofthe one or more openings;

injecting a fluid mouldable material into said mould cavity;

allowing the material to set to thereby form the outer coating;

separating the formed device from the mould cavity.

The core may be prepared by compressing suitable ingredients for thecore to form a compacted mass which comprises the core of the device(also referred to herein as “tablet core”). This may be prepared usingconventional tablet excipients and formulation compression methods.Thus, the core would typically comprise the active agent or agents alongwith excipients that impart satisfactory processing and compressioncharacteristics such as diluents, binders and lubricants. Additionalexcipients that may form part of the core of the device includedisintegrants, flavourants, colorants and release modifying agents.Typically the active agent and excipients are thoroughly mixed prior tocompression into a solid core. The core of the device can be formed byconventional tablet-forming processes such as wet granulation methods,dry granulation methods or by direct compression. The core can beproduced according to any desired pre-selected shape such as bi-convex,hemi-spherical, near hemi-spherical, round, oval, generally ellipsoidal,oblong, generally cylindrical or polyhedral, e.g. a triangular prismshape.

A preferred shape of core is one which is generally of cylindrical shapehaving two opposite facing generally convex circular end faces. Suchconvex end faces may be of a generally part-spherical domed convexshape, or generally conical or frustro conical. Another preferred shapeof core is a convex or of a bi-convex shape comprising twoopposite-facing domed surfaces which are generally circular orelliptical in plan.

The term “near hemi-spherical” is intended to be construed in the mannerdescribed in U.S. Pat. No. 5,004,614. The term “cylindrical” is intendedto include both true cylindrical shapes and distorted cylindricalshapes. Preferably the core is formulated into a bi-convex shape, e.g.having two domed opposite surfaces. If the core has corners, e.g.corners between cylindrical side surfaces and convex end surfaces, arounded corner radius of ca. 1 mm is preferred to assist flow of thefluid coating material during injection.

The core could be produced in a multi-layered (e.g. bi- or tri-layered)form.

The delivery device of the invention is most suitable as an oraldelivery device, as it can conveniently be made in the shape and size ofa pharmaceutical tablet, well known to those acquainted withpharmaceutical technology. The core can comprise active agents which aresuitable for use in a wide range of therapies, particularly for oraldelivery, and include those listed U.S. Pat. No. 5,004,614. The quantityof active agent present within the core is a matter to be determinedbased upon typical pharmaceutical considerations, e.g. known dosages forthe active materials contained therein, and is not limited by theprocess of this invention or the structure of the delivery devicesformed thereby.

It will be appreciated that to carry out the process of this invention,the tablet core must be accurately located within the mould cavity tothereby achieve a precisely defined thickness of coating and/orpositioning of the one or more opening. Preferably the tablet core islocated via robotic means.

The core of the device is coated with a suitable material by aninjection moulding process. Injection moulding generally involves theinjection of a molten thermoplastic, fluid-like material, often a fluidpolymer under pressure and usually at an elevated temperature, into aprecisely made die cavity in a mould block. Upon cooling, typically toambient temperature, the fluid material solidifies to form a solidproduct reproducing the internal shape of the cavity. Alternatively theinjection moulding process may use a thermosetting fluid-like material,for example injecting the material in a fluid state into a heated mould,where the heat acts upon the thermosetting material to solidify it.Silicone materials are known thermosetting materials. Such mouldingtechniques are well known in the art of manufacture of small plasticmaterial components. Typical injection moulding apparatus comprise apolymer feed system, consisting of a polymer reservoir, e.g. a hopper ofpolymer pellets or granules, a heater and a screw pump that forces thefluid polymer down an injection port towards the mould.

The injection moulding process of this invention can be carried out on astandard injection moulder, e.g. of a hot or cold runner type. A hotrunner system is preferred, and although valve gates could be used toeliminate the gate pip, in practice the very small residual gate pipleft by conventional hot runner machines is likely to be insignificant.Such apparatus is capable of operating over a wide range of temperaturesand pressures. It will be appreciated however, that a principal factoraffecting the utility of this invention is the capability of the tabletcore to withstand the rigours of injection moulding conditions. Forexample many pharmaceutically active agents are complex organiccompounds which are susceptible to thermal degradation at elevatedtemperatures, which may be exacerbated by simultaneous application ofhigh pressure. Therefore it is preferred to use temperatures for theinjection moulding process which are considered to minimise or ideallyavoid any thermal degradation for the active agent in question. For manysuch agents suitable processing conditions to achieve this are specifiedin the literature. For these reasons, it is believed that typicaloperational conditions would be between temperatures of 25-300° C., moretypically 50-250° C. and especially 50-150° C. Preferably the injectionmoulding pressure should be less than 6000 psi (ca. 400-450 kg/cm²) toavoid damage to a tablet core within the mould cavity, typicallypressures of 200 to 1000 psi (ca. 14-70 kg/cm²), more typically 400 to600 psi (ca. 30-45 kg/cm²) have been found suitable. Conversely thetablet core should be made of materials and using suitable conditionsthat the core can withstand such pressures within the mould withoutbreaking or crumbling.

The material of the outer coating may be any material which blocks(either permanently of for a suitable time period) exposure of the coreto an environmental fluid, e.g. a gastro-intestinal fluid, and is notremoved by dissolution or otherwise disrupted before a predeterminedduration for controlled, delayed or sustained release of the activematerial in the core has occurred. Alternatively, the coating materialmay be selected because of aesthetic considerations. Anypharmaceutically acceptable fluid mouldable material which exhibitsthermoplastic properties can be used as an outer coating for the tabletcore, and suitable materials include thermoplastic organic polymers.Those skilled in the art of injection moulding characterise the flowproperties of polymeric materials according to a melt flow index whichranges from 1 g/10 min (very poor flow) to 50 g/10 min (very high flow).It has been found that materials that exhibit a melt flow index in therange of 15-30 g/10 min are particularly suitable for use in thisinvention. Representative materials and their blends suitable for use asa coating material in this invention include those listed in U.S. Pat.No. 5,004,614. Preferred coating materials include the polymethacrylatecopolymers, natural waxes and lipids, and biodegradable polymers ingeneral. Other suitable polymer materials include polyvinyl acetates,such as the 40 and 20 grades thereof, cellulose acetate, butyrate andphthalate, EVA (ethylene vinyl acetate) or HPC (hydroxypropylcellulose), silicones, or copolymers of methacrylic acid,methylmethacrylate, and methyl acrylate, such as that known as 4135F,available from Röhm polymers, or a blend based on 4135F. 4135F comprisesa methacrylic acid, methylmethacrylate, methyl acrylate copolymer in atypical ratio 25:65:10 with a dissolution threshold of pH greater than7.2.

Accordingly in a further aspect, the present invention provides a deviceadapted for oral delivery of a pharmaceutically active agent, when madeby a process as described herein. Typically such a device comprises acore which includes a pharmaceutically active agent covered by an outercoating which includes one or more openings communicating from theexterior of the device to the core characterised in that the outercoating is a polymeric material exhibiting a melt flow index whichranges from 1 g/10 min (very poor flow) to 50 g/10 min (very high flow),especially that exhibits a melt flow index in the range of 15-30 g/10min, applied by injection moulding said coating around said core.

The thickness of the outer coating can be readily adapted. For devicessuch as those described in U.S. Pat. No. 5,004,614 it is important that,for materials that do exhibit a certain degree of permeability toenvironmental fluids, that the coating is applied at such a thickness toprevent exposure to the core before the desired duration of thecontrolled release has passed. For immediate release devices aconsiderably thinner coating could be utilised or a coating appliedwhich is designed to dissolve in gastrointestinal fluid. It is believedthat a suitable coating thickness that can be achieved by this processof this invention is the range of 0.1 mm to 2 mm, preferably in therange 0.2 to 0.8 mm, more preferably in the range 0.1 to 0.6 mmTypically tablet cores may be made with a tolerance of ±0.025 mm on acylindrical diameter, and ±0.1 mm on a cylindrical height. Typicallythere might be variation of less than 0.03 mm in an injection mouldcavity, and these figures indicate typical tolerance ranges for thethickness of the coating achievable by the process of this invention. Animportant factor to consider is the melt flow index of the thermoplasticpolymer. Thus, to obtain the thinnest coating section it will benecessary to use a polymer with a high melt flow characteristics. Evensmall thickness variations can have significant effects on melt flow,and as a coating thickness of nominally 0.6-0.4 mm appears to be optimumfrom the point of view of the moulding process, although pharmaceuticalrequirements of the delivery device might require other thicknesses.

A mould suitable for use in the process of this invention has a cavityin which the tablet core may be located with a space around the saidcore to define the required shape and dimensions of the coating, withone or more internal member extending from the interior surface of themould cavity to abut the said core and to define the shape and positionof the said one or more opening. Typically the mould will incorporateplural cavities to maximise the production rate of the process, as isstandard practice in the injection moulding art. Typically the mouldmight include 16 cavities. The internal members define the openings ofthe device. Such internal members are preferably designed without anyoverhang between them and the interior surface of the mould cavity, sothat they can be easily separated from the device produced thereinwithout any damage occurring to the coating. These internal members mayalso serve to hold the core in place as the fluid coating material isinjected into the mould cavity.

In a preferred construction of mould, one or more internal member isresiliently mounted, e.g. spring-mounted, so as to be able to movereciprocally resiliently inward and outward relative to the mouldcavity. By this construction such a resilient internal member can applya resilient pressure to a core when enclosed in the mould cavity to helpto hold the core in place within the mould cavity. Also the ability ofsuch a member to move slightly when it contacts a tablet core on closingthe mould can help to relieve any pressures on the core which might tendto break the core, and can help the internal member to accommodate tovariations in the size between tablet cores. Preferably the resilientmounting of such an internal member should be such as to apply aresilient pressure of up to 200 psi (ca. 14 kg/cm²) to the tablet core,or conversely to be resiliently moveable under such a pressure appliedthereto.

It is also preferred to provide an internal member with a vacuum conduitpassing therethrough to the outside of the mould, by which reducedpressure may be applied to a tablet core in contact with the member toassist in retaining the core in place in the mould. Suitably the vacuumconduit may pass through a resiliently mounted internal member asdescribed above. Such a vacuum conduit may be useful both in mouldswhich close along a horizontal axis such that the reduced pressureprevents the cores from falling out of the cavity, and also moulds whichclose along a vertical axis so that the reduced pressure supplementsgravity in holding the core in place.

Normally an injection mould has one fixed part and a second moving partwhich moves into contact with the fixed part to close the mould.Suitably the resilient member and any vacuum conduit could be on thisfixed part.

For use with a mould as described above having an internal member it ispreferred to provide the core with at least one small seatingindentation of a shape generally corresponding to the part of the memberthat contacts the core, and so positioned on the core that when themould encloses a tablet core, the member seats in the indentation. Thiscan help to positively locate the core in the mould cavity and to securethe core in place in the mould cavity. In the above-described bi-convexcore such an indentation may be located on one or both of the convexsurfaces, e.g. the convex end surfaces of the generally cylindricalcore. Such an indentation may be need to be at most 1.5 mm deep, andpreferably for example may need to be only ca. 0.005 cm deep. Suitablysuch an indentation is tapered to be narrowest at its bottom, e.g.having a frustro-conical profile. The core may also be provided with oneor more, preferably at least three small seating projections e.g. ribs,to engage with the inner surface of the mould cavity, e.g. withcorresponding concavities therein, to assist in locating the core withinthe mould cavity. Such projections may be shaped to make only a pointcontact with the mould cavity so as to avoid resulting in the formationof any corresponding opening through the coating.

Generally the mould cavity is made in a multi-part, preferably a twopart mould construction, which close together with great precision,where each part defines a respective part of the mould cavity. Whenassembled together the two mould parts define an internal cavity i.e.such that, on closure, a cavity around the tablet core is defined whichcorresponds to the required dimensions of the coating. Such aconstruction further allows the mould cavity to be opened to allow theformed device to be separated from the mould. Moulds of this generaltype for use in injection moulding processes are well known in the art.The one or more internal members can be located at any suitable positionon the inner wall surface of the mould cavity and are preferably madeintegral with the mould. Where a multi-part construction is utilised theinternal members may be located upon one or more mould parts. The partsof such a multi-part mould may close horizontally, i.e. along ahorizontal axis, or vertically, i.e. along a vertical axis. Ahorizontally closing mould is preferred.

The mould may also incorporate one or more pairs of retractable sidecores which can move together to grip a tablet core when the core hasbeen located in a part of the mould, to help to hold the core in placeuntil the mould is fully closed. Such side cores may be particularlyuseful in a horizontally closing mould.

A typical process of the invention may involve the steps (1) loadingtablet cores into a feeder, e.g. a vibratory bowl feeder, for dischargeonto one or more conveyor, from which the tablet cores can be collectedin the alignment required for picking up by a robot equipped withsuction grippers, (2) the robot placing the tablet cores onto a registerstation to accurately position them in the spatial arrangement requiredfor insertion into the mould cavities, (3) a robot picking up the tabletcores and inserting them into the mould cavities, (4) performing theinjection of coating material, (5) if a vertically closing mould isused, removing the completed devices from the mould cavities using arobot. Step (2) might be eliminated, e.g. by designing a collectiondevice at the end of the conveyor with sufficient accuracy thatsubsequent alignment on a register is not required. Steps (3) and (4)might be combined by designing a robot with two sets of grippers, one tohold the tablet cores and one to hold the completed articles, so whilstthe mould is open the gripper head could extract the completed devices,index sideways, and place new tablet cores into the cavities.

The invention also provides, in a further aspect, a die or mouldsuitable for use in the moulding process, which has a cavity in which atablet core may be located and being of dimensions such as to leave aspace around the said core to define the required shape and dimensionsof the coating, with one or more internal members extending from theinterior surface of the mould cavity to abut the said core.

It will be appreciated that the required shape, size, number of openingsand the geometric arrangement of openings required for the device can bereadily achieved by a suitable arrangement of the shape, size, numberand relative positions of the internal members(s) on the mould or mouldpart. Any single opening can be as fine as 0.1 um and up to as large asa face of the tablet core e.g. 10 mm. Typical openings would be in therange 0.5 mm-4 mm. Preferably, the opening(s) of the device willcomprise about 10-60% of the total face area of the device. The openingmay have any convenient shape, but is preferably rounded, e.g.substantially circular or elliptical.

For example, in one embodiment the device may comprise a core which isgenerally of cylindrical shape having two opposite facing substantiallycircular end faces or of a bi-convex shape comprising twoopposite-facing domed surfaces which are generally circular orelliptical in plan, covered with an outer coating which generallyconforms to the outer shape of the core, the coating having two oppositefacing openings therein communicating with substantially the centre ofeach of said respectively substantially circular or domed surfaces.

The injection moulding process of this invention can be used to producea device which can be used for immediate, delayed or sustained release,for example to achieve release of the active agent at a pre-determinedpart of the gastrointestinal tract. Those skilled in the art, whenconsidering the release profile of a device containing an active agent,would consider factors such as drug solubility, the surface area andnumber of openings, coating thickness and the tablet core formulationproperties. It will be appreciated that such variations in device can bereadily accommodated by the process of this invention.

This process differs from known methods inter alia in that the coatingis applied to create the device in a single operation i.e. no furtherprocessing of the coating is required such as mechanical drilling of thecoat to expose the core. It permits an improved method of producingdevices with a varying number, size and shape of openings. Moreover, theaccuracy of opening size is more reproducible. It is believed that thisprocess is more robust and simpler to operate than known methods and isparticularly suitable for mass production of such devices.

The invention will now be described by way of example only withreference to the accompanying drawings.

FIGS. 1 to 3 schematically shows sequential stages in the use of theprocess to make a device in accordance with this invention.

FIGS. 4 and 5 show a device as made using the process of this invention.

FIG. 6 shows a preferred injection mould for the process of theinvention.

FIG. 7 shows a preferred shape of tablet core.

With respect to FIGS. 1 to 3, a tablet core 1 is shown within a mouldoverall 2, made in two mating halves 2A and 2B. The core 1 is of agenerally cylindrical shape having two opposite facing substantiallycircular end faces and cylindrical side walls, and FIG. 1 shows thiscylindrical core in longitudinal section. The mould defines a cavity 3which defines the shape of the coating to be applied to the tablet core,each of the two halves 2A and 2B defines a part cavity so that when thetwo halves 2A and 2B are put together the entire cavity 3 is defined.The cavity 3 conforms closely to the shape and dimensions of the core 1,but leaves a gap around the core 1 which subsequently defines thethickness of the coating to be formed therein.

Extending from the inner wall of the mould cavity 3 are internal membersbeing projections 4 integrally formed with the mould parts 2A and 2B.These projections 4 abut against the core 1 when this is within themould cavity 3, and serve both to hold the core in place within thecavity, preventing the core from being dislodged when coating materialis injected into the cavity, and to define the size, shape and positionof the openings to be formed in the coating. These projections 4 areshaped without any overhang between them and the inner wall of the mouldcavity, to allow the projections to be removed from the subsequentlyformed coating without damaging the coating. Suitably the projections 4may taper, being narrowest at the end remote from the inner wall of themould cavity.

In FIG. 1 the mould 2 is shown in an open configuration, with a fixedmould part 2A lowermost, and the tablet core 1 resting on theprojection. In FIG. 2 the mould 2 has been closed, so that theprojection 4 of the upper mould part 2B has come into contact withtablet core 1.

In FIG. 3 a molten coating material 6 has been injected into the cavity3 via injection port 5 positioned at a convenient point on the fixedpart 2A of the mould 2. Following cooling the two mould parts 2A and 2Bare opened and the formed device 7 is ejected.

The device 7 is shown in cross section and a plan view respectively inFIGS. 4 and 5, and comprises the core 1, enclosed by the coating 6,through which extend the two openings 8 corresponding to the respectivepositions of the two projections 4.

In FIG. 6 a preferred construction of mould 20 is shown in crosssection. This has two parts 20A, 20B corresponding to those 2A, 2B ofmould 2. These parts 2A, 2B have internal projections 24A, 24Bcorresponding to those 4 of mould 2. Each projection 24A, 24B is of afrustro conical shape, widest at its base where it meets the innersurface of the mould cavity 23. The projection 24A in the fixed part 20Ais resiliently reciprocally moveable in the direction of the arrows,under the biasing action of a spring (not shown) bearing upon its end24C outside the mould part 20A, and the projection 24A is slideablymounted in a guide channel 25 passing through the mould part 20A (theclearance in the channel 25 between the part 24A and the mould part 20Ais exaggerated for clarity). The resilient mounting of the projection24A is such as to move under a downward pressure of ca. 200 psi from atablet core (not shown) bearing thereon. Passing through projection 24Ais a vacuum conduit 26, via which a partial vacuum can be applied tosuch a tablet core resting on projection 24A downwards. There is aninjection gate 27 in the lower fixed mould part 24A for injection offluid coating material.

Referring to FIG. 7 a preferred tablet core shape 71 is shown in plan(FIG. 7A) and in side view (FIG. 7B). The shape is generallycylindrical, with a cylindrical part 72 having spherically domed convexend faces 73, 74. In each face 73, 74 is an indentation 75, 76 of aprofile each matching the convex frustro-conical profile of theprojections 24A, 24B of the mould 20. The slope of the conical sides ofthese indentations is ca 35° relative to the longitudinal cylindricalaxis of the core 71. The diameter of the outer rim of each indentation75, 76 is ca. 70-75% of the overall diameter of the cylindrical shape,and the depth in the longitudinal direction is ca. 0.4 mm.

EXAMPLE 1

The following tablet cores were formed by conventional means by mixingtogether the active ingredients with excipients and compressing to formthe tablet core. These examples are intended to be by way ofillustration rather than limitation.

Tablet core a) represents a core that is suitable for use in animmediate release formulation which consists of 10% active ingredient,60% microcrystalline cellulose, 24% lactose, 5% starch glycolate(disintegrant) and 1% magnesium stearate (lubricant).

Tablet b) represents a core that is suitable for use in a controlledrelease formulation which consists of 10% active ingredient, 40%hydroxypropylmethyl cellulose (HPMC), 24% lactose, 20% microcrystallinecellulose, 5% starch glycolate and 1% magnesium stearate.

The coating material used was a low density polyethylene produced byExxon Chemical. The grade was LD600BA natural. This materialdemonstrates a wide range of processing temperatures (160 to 240° C.)and has a melt flow index of 20.5 g/10 min. Operating conditionsutilised were 150° C. and pressure of 400 psi.

The injection moulding machine used was a 35T Arburg.

The tablet cores shown in FIGS. 1 to 5 and 7 typically had a diameter of8 mm. The coating had a thickness, as defined by the gap in the cavitybetween the core and the inner wall of the cavity of ca. 0.5 mm. Theopenings 7 in the coating were typically circular in shape having adiameter of 1 mm, or ca. 6 mm using the core shape shown in FIG. 7.

It has been found that these injection moulding operating conditions didnot have an adverse effect on the tablet core i.e. mechanical integritywas maintained.

1. A process for the preparation of a device comprising a core whichincludes a pharmaceutically active agent covered by an outer coatingwhich includes at least one opening communicating from the exterior ofthe device to the core, in which the outer coating is applied byinjection molding said coating around said core, the process comprising:locating said core within a mold cavity surrounding the core, said moldcavity defining the required dimensions of the outer coating and alsodefining the required position, shape and dimensions of each saidopening; injecting a fluid moldable thermoplastic material into saidmold cavity; allowing the fluid moldable thermoplastic material to set,thereby forming the outer coating; and separating the device, comprisingthe core, the outer coating, and said at least one opening, from themold cavity, in which the mold cavity has an interior surface, in whicha space is provided between said interior surface of the mold cavity andthe core, said space defining the required shape and dimensions of thecoating, in which an internal member extends from the interior of themold cavity, through each said opening during injection and setting ofthe fluid moldable thermoplastic material, to abut the said core and todefine the shape and position of the opening through which the internalmember extends, and in which part of said at least one said internalmember is located outside the mold, and said at least one said internalmember extends from the exterior of the mold into the mold cavity and ismounted for inward and outward movement relative to the mold cavity andresiliently biased against said core during injection and setting of thefluid moldable thermoplastic material.
 2. A process according to claim1, in which said fluid moldable material is injected at a pressure lessthan 400-450 kg/cm².
 3. A process according to claim 1, wherein said atleast one internal member is resiliently moveable under a pressure ofnot more than 14 kg/cm² applied thereto.
 4. A process according to claim1, wherein a reduced pressure is applied through a vacuum conduitextending through said at least one internal member from the inside tothe outside of the mold, and said reduced pressure is applied to saidcore, while the core is in contact with said at least one internalmember, to assist in retaining the core in place in the mold.
 5. Aprocess for the preparation of a device comprising a core which includesa pharmaceutically active agent covered by an outer coating whichincludes at least one opening communicating from the exterior of thedevice to the core, in which the outer coating is applied by injectionmolding said coating around said core, the process comprising: locatingsaid core within a mold cavity surrounding the core, said mold cavitydefining the required dimensions of the outer coating and also definingthe required position, shape and dimensions of each said opening;injecting a fluid moldable thermoplastic material into said mold cavity;allowing the material to set, thereby forming the outer coating; andseparating the device, comprising the core, the outer coating, and saidat least one opening, from the mold cavity, in which the mold cavity hasan interior surface, in which a space is provided between said interiorsurface of the mold cavity and the core, said space defining therequired shape and dimensions of the coating, in which an internalmember extends from the interior of the mold cavity, through each saidopening during injection and setting of the fluid moldable thermoplasticmaterial, and has a convex end face comprising a substantiallyfrusto-conical surface and an end face transverse to said frusto-conicalsurface, the internal member defining the shape and position of theopening through which the internal member extends, in which a vacuum isdrawn through a vacuum channel extending through at least one saidinternal member to an opening in said end face, and, in which the corehas a seating indentation comprising a concave frusto-conical surfacereceiving and fitting to the frusto-conical surface of said convex endface, and a transverse surface in abutment with said transverse end faceso that, when the mold encloses the core, the internal member seats inthe indentation.
 6. A process according to claim 1, in which said atleast one internal member is resiliently biased against said core by thebiasing action of a spring located outside the mold.